Metabolism of paracetamol

Glutathione is also implicated in the removal of toxic metabolites from the analgesic paracetamol (USA acetaminophen). Oxidative metabolism of paracetamol produces an A-hydroxy derivative, and this readily loses water to generate a reactive and toxic quinone imine, which interacts with proteins to cause cell damage. 

Figure 7.10 Metabolism of paracetamol. With therapeutic doses, paracetamol is metabolised to the glucuronide and sulphate conjugates. With higher doses these pathways become saturated and metabolism proceeds via die P-450-mediated route, with the formation of the toxic metabolite benzoquinone. This is normally metabolised by conjugation with glutathione. When glutathione is depleted benzoquinone is free to interact with cellular macromolecules, leading to cellular damage.

Studies in human subjects have revealed that there is considerable variation between individuals in their rate of metabolism of paracetamol via the toxic, oxidative pathway. Thus, at one end of the frequency distribution, some individuals, approximately 5% of the particular population studied, metabolized paracetamol at a rate similar to hamsters and mice. Other individuals at the opposite end of the frequency distribution have rates of oxidation about one-quarter of the highest rates, and these individuals are probably more akin to rats, the resistant species. 

Large molecule cryoprobe applications predominated during 2004. The only other paper of which the author is aware was a study by Godejohann et al.263 involving a study of the metabolism of paracetamol using online LC-SPE-NMR-MS which utilized a cryoflow probe. 

The metabolism of paracetamol (Figure 6.6) is an example of potential toxication. Paracetamol is metabolised primarily in the liver, via phase II metabolism, where its major metabolites include inactive sulphate and glucuronide conjugates, which are excreted by the kidneys. 

In animals, chronic ethanol causes induction of hepatic microsomal enzymes, and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoenzyme is important in the oxidative metabolism of paracetamol). This conclusion is not yet fully documented in man. 

Theoretically these drugs could increase the metabolism of paracetamol to NAPQI, and could increase the risk of hepatotoxicity. 

Al-O Baidy SS, McKiernan PJ, Li Wan Po A, et al. (1996) Metabolism of paracetamol in children with chronic liver disease. Eur J Clin Pharmacol 50 69-76. 

Leung NW, Critchley JA (1991) Increased oxidative metabolism of paracetamol in patients with hepatocellular carcinoma. Cancer Lett 57 45—48. 

S-glutathionyl)paracetamol Figure 2 Metabolism of paracetamol (acetaminophen). 

Food slows the rate of absorption of paracetamol, but the overall bioavailability is not usually affected. However, in some individuals food may delay and reduce peak paracetamol-plasma levels. A high fat meal may slightly reduce the extent of paracetamol absorption and certain foods, such as cabbage and brussels sprouts, may affect the metabolism of paracetamol, but this is unlikely to be clinically significant. 

In a crossover study in 10 healthy subjects, a 10-day balanced diet including cabbage 1(X) g and brussels sprouts 150 g at lunch and dinner was found to stimulate the metabolism of paracetamol, at least in part by en-... 

Any changes in the pharmacokinetics of paracetamol with these H2-recep-tor antagonists appear to be clinically unimportant. Thus, no special precaution would seem to be necessary when paracetamol is used with cimetidine, nizatidine or ranitidine. The effect of cimetidine on the oxidative metabolism of paracetamol has been investigated as a means of reducing paracetamol hepatotoxicity. However, it appears that cimetidine is not effective for this purpose. ... 

A number of reports surest that the toxicity of paracetamol may be increased by isoniazid so that normal analgesic dosages (4 g daily) may not be safe in some individuals. Pharmacokinetic studies surest that isoniazid usually inhibits the metabolism of paracetamol, but that metabolism to toxic metaboUtes may be induced shortly after stopping isoniazid, or late in the isoniazid dose-interval in fast acetylators of isoniazid. 

Epstein MM, Nelson SD, Slattery JT, KaUiom TF, Wall RA, Wright JM Inhibition of the metabolism of paracetamol by isoniazid. BrJ Clin Pharmacol (1991) 31,139-42. 

The changes described here appear to be small, and therefore unlikely to be clinically significant. Note that, it has been postulated, based on studies in animals, that propranolol may have a protective effect on paracetamol hepatic toxicity by inhibiting the oxidative metabolism of paracetamol to toxic metabolites. ... 

Rifampicin increasesi the metabolism of paracetamol. An isolated report describes hepatic faiiure, which may have been due to an interaction between paracetamoi and rifampicin. 

Heavy, but not moderate, smoking may increase the metabolism of paracetamol. The clearance of phenacetin is also increased in smokers. There is some evidence that smokers are at risk of a poorer outcome after paracetamol overdose. 

Paracetamol No significant effect on the pharmacokinetics of paracetamol was found in one study but another small study found that the metabolism of paracetamol was reduced. Unlikely to be clinically significant. 36,37... 

The main interactions of aspirin and the salicylates were reviewed in SED VIII (p. 174). New papers have appeared on interactions with various anti-flammatory drugs, though data on indomethacin in this connection are contradictory (168 -172 ). There may be species differences in these interactions (172 ). Plasma concentrations of salicylate are markedly reduced (30—70%) by antacids as a result of increased urine pH and enhanced renal clearance of salicylate (173 ). In guinea pigs aspirin enhances the metabolism of paracetamol to the hepatotoxic metabolite which is excreted in the urine as paracetamol mercaptu-ric acid (174). This interaction may potentiate the toxicity of phenacetin and paracetamol. 

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